Direct Enantioselective α-C–H Conjugate Addition of Propargylamines to α,β-Unsaturated Ketones via Carbonyl Catalysis

作者：Ruixin Zhang, Jiwei Xu, Siqi Liu, Shibo Si, Jiayao Chen, Lingxiao Wang, Wenwen Chen, Baoguo Zhao · 发表于：Journal of the American Chemical Society · 年份：2024 · DOI：10.1021/jacs.4c09840 · 被引用次数：32 · 研究领域：Catalytic C–H Functionalization Methods、Asymmetric Synthesis and Catalysis、Catalytic Alkyne Reactions

Direct asymmetric α-C–H conjugate addition of propargylamines to α,β-unsaturated ketones remains a great challenge due to the low α-amino C–H acidity of propargylamines and the nucleophilic interference of the NH 2 group. Utilizing a new type of pyridoxals featuring a benzene-pyridine biaryl skeleton and a bulky amide side chain as carbonyl catalyst, we have accomplished direct asymmetric α-C–H conjugate addition of NH 2 -unprotected propargylamines to α,β-unsaturated ketones. The adducts undergo subsequent in situ intramolecular cyclization, delivering a wide range of chiral polysubstituted 1-pyrrolines in high yields (up to 92%) with excellent diastereo- and enatioelectivities (up to >20:1 dr and 99% ee). This work has demonstrated a straightforward approach to access pharmaceutically important chiral 1-pyrrolines, and it has also provided an impressive instance of direct asymmetric functionalization of inert C–H bonds enabled by biomimetic organocatalysts.